1. Field of Invention
The present invention relates generally to medical devices and methods for inhibiting restenosis in a blood vessel after an initial treatment for opening a stenotic region in a blood vessel. More particularly, the present invention relates to combination x-ray radiation and drug delivery devices for inhibiting hyperplasia following balloon angioplasty and other interventional treatments.
A number of percutaneous intravascular procedures have been developed for treating stenotic atherosclerotic regions of a patient""s vasculature to restore adequate blood flow. The most successful of these treatments is percutaneous transluminal angioplasty (PTA). In PTA, a catheter, having an expansible distal end usually in the form of an inflatable balloon, is positioned in the blood vessel at the stenotic site. The expansible end is expanded to dilate the vessel to restore adequate blood flow beyond the diseased region. Other procedures for opening stenotic regions include directional atherectomy, rotational atherectomy, laser angioplasty, stenting, and the like. While these procedures have gained wide acceptance (either alone or in combination, particularly PTA in combination with stenting), they continue to suffer from significant disadvantages. A particularly common disadvantage with PTA and other known procedures for opening stenotic regions is the frequent occurrence of restenosis.
Restenosis refers to the re-narrowing of an artery after an initially successful angioplasty. Restenosis afflicts approximately up to 50% of all angioplasty patients and is the result of injury to the blood vessel wall during the lumen opening angioplasty procedure. In some patients, the injury initiates a repair response that is characterized by smooth muscle cell proliferation referred to as xe2x80x9chyperplasiaxe2x80x9d in the region traumatized by the angioplasty. This proliferation of smooth muscle cells re-narrows the lumen that was opened by the angioplasty within a few weeks to a few months, thereby necessitating a repeat PTA or other procedure to alleviate the restenosis so that blood perfusion may be restored.
A number of strategies have been proposed to treat hyperplasia and reduce restenosis. Previously proposed strategies include prolonged balloon inflation during angioplasty, treatment of the blood vessel with a heated balloon, stenting of the region, use of radiotherapy to treat in-stent restenosis, the administration of therapeutic drugs following angioplasty, and other procedures. While these proposals have enjoyed varying levels of success, no one of these procedures is proven to be entirely successful in completely avoiding all occurrences of restenosis and hyperplasia.
As an alternative to the above mentioned therapies, the combination of radioisotope radiation and drug therapy following PTA for the inhibition of hyperplasia has also been proposed. Drug therapy infuses or releases a drug through a catheter or from a stent, while intravascular radiotherapy may configure catheters, guidewires, and stents to position a solid radioisotopic source (such as a wire, strip, pellet, seed, bead, or the like). While combination delivery of therapeutic agents with radioisotopic sources holds promise, there may be circumstances where certain agents and sources would be particularly advantageous.
For these reasons, it would be desirable to provide improved devices and methods for inhibiting restenosis and hyperplasia following angioplasty and other interventional treatments. In particular, it would be desirable to provide improved devices, methods, and kits for drug delivery in combination with x-ray radiation delivery to a blood vessel to reduce and/or inhibit restenosis and hyperplasia rates with increased efficacy. It would further be desirable to provide such devices and methods which significantly reduce dose concentrations of drugs and/or radiation within the vessel wall while delivering sufficiently uniform radiation dosages and promoting endothelialization of the vessel wall. At least some of these objectives will be met by the devices and methods of the present invention described hereinafter.
2. Description of Background Art
Full descriptions of exemplary x-ray sources for use in the present invention are described in co-pending U.S. patent application Ser. No. 09/299,304, assigned to the assignee herein, and U.S. Pat. No. 6,095,966, licensed to the assignee herein. Devices and methods for exposing intravascular and other treatment locations to radioisotopic materials in combination with therapeutic drugs are described in the following: U.S. Pat. Nos. 6,149,574; 5,993,374; 5,951,458; and International Publication Nos. WO 00/47197; WO 00/00238; WO 99/55285; WO 99/51299; WO 98/36790; and WO 96/23543. The use of texaphyrins for radiation sensitization is described in U.S. Pat. No. 6,072,038. Devices and methods for exposing intravascular locations to radioactive materials are described in the following: U.S. Pat. Nos. 6,069,938; 5,971,909; 5,653,736; 5,643,171; 5,624,372; 5,618,266; 5,616,114; 5,540,659; 5,505,613; 5,503,613; 5,498,227; 5,484,384; 5,411,466; 5,354,257; 5,302,168; 5,256,141; 5,213,561; 5,199,939; 5,061,267; and 5,059,166, European applications 860 180; 688 580; 633 041; and 593 136, and International Publications WO 97/07740; WO 96/14898; and WO 96/13303. Drug delivery within the vasculature is described in U.S. Pat. Nos. 6,099,561; 6,071,305; 6,063,101; 5,997,468; 5,980,551; 5,980,566; 5,972,027; 5,968,092; 5,951,586; 5,893,840; 5,891,108; 5,851,231; 5,843,172; 5,837,008; 5,769,883; 5,735,811; 5,700,286; 5,681,558; 5,679,400; 5,649,977; 5,637,113; 5,609,629; 5,591,227; 5,551,954; 5,545,208; 5,500,013; 5,464,450; 5,419,760; 5,411,550; 5,342,348; 5,286,254; and 5,163,952. Biodegradable materials are described in U.S. Pat. Nos. 5,876,452; 5,656,297; 5,543,158; 5,484,584; 4,897,268; 4,883,666; 4,832,686; and 3,976,071.
The disclosure of this application is related to the disclosures of the following applications being filed on the same day: Ser. No. 09/851,372 and Ser. No. 09/850,728.
The full disclosures of each of the above references are incorporated herein by reference.
The present invention provides improved devices, methods, and kits for inhibiting restenosis and hyperplasia after intravascular intervention. In particular, the present invention provides controlled drug delivery in combination with x-ray radiation delivery to selected locations within a patient""s vasculature to reduce and/or inhibit restenosis and hyperplasia rates with increased efficacy. The methods and apparatus of the present invention can significantly reduce dose concentrations of drugs and/or radiation within the vessel wall while delivering sufficiently uniform radiation dosages and promoting endothelialization of the vessel wall.
The term xe2x80x9cintravascular interventionxe2x80x9d includes a variety of corrective procedures that may be performed to at least partially resolve a stenotic condition. Usually, the corrective procedure will comprise balloon angioplasty. The corrective procedure could also comprise atherectomy, rotational atherectomy, laser angioplasty, stenting, or the like, where the lumen of the treated blood vessel is enlarged to at least partially alleviate a stenotic condition which existed prior to the treatment. The corrective procedure could also involve coronary artery bypass, vascular graft implantation, endarterectomy, or the like.
By xe2x80x9ccontrolledxe2x80x9d drug delivery, it is meant that a predetermined amount of a drug or agent is released or delivered at a predetermined rate to a blood vessel. Typically, such controlled delivery maintains a steady-state concentration of the drug in a vascular environment within a desired therapeutic range of time, e.g. hours, days, weeks, or in some cases months.
In a first aspect of the present invention, a combination radiation and agent delivery catheter for inhibiting hyperplasia generally comprises a catheter body having a proximal end and distal end, an x-ray tube coupleable to the catheter body for applying a radiation dose to a body lumen, and means coupleable to the catheter body for releasing an agent to the body lumen. The body lumen may be any blood vessel in the patient""s vasculature, including veins, arteries, aorta, and particularly including peripheral and coronary arteries.
The means may comprise a source of at least one agent selected from the group consisting of radiosensitizer, immunomodulator, cytotoxic agent, cytostatic agent, anti-restenotic agent, and anti-inflammatory agent. The agent may also be a prodrug (e.g., precursor substances that are converted into an active form in the body) of any of the above described agents. Preferably, the means comprises a source of at least one radiosensitizer or immunomodulator. Radiosensitizers may be selected from the group consisting of taxol, misonidazole, metronidazole, etanidazole, 5-fluorouracil, texaphyrin, C225 (an anti-EGFR monoclonal antibody), and cyclooxygenase-2 inhibitor. Immunomodulators may be selected from the group consisting of rapamycin, beta interferon, alpha interferon, methotraxate, cyclosporine, six-mercaptopurine, and cimetidine. More preferably, the means comprises a source of rapamycin, beta interferon, and/or taxol, incorporated in a solution with polyoxyethylated castor oil and dehydrated alcohol. The agent may also be attached or encapsulated in a lipid or surfactant carrier.
The combination of drugs and x-ray radiation therapy reduces and/or inhibits restenosis and hyperplasia rates with increased efficiency. In some instances, at least, it will be expected that the x-ray dosage will provide an immediate inhibition of cell proliferation while the drugs, which may be released over relatively long periods of time, e.g. days, weeks, or in some cases months, will provide prolonged inhibition. In particular, it will be appreciated that many of the above described agents may perform a variety of functions, including minimizing proliferative/restenotic activity, promoting endothelialization of the vessel wall, which is needed for healing, providing synergistic enhancement to radiation effects, and the like. Furthermore, a combined balance of both therapies allows for reduced dosages/concentrations of radiation and/or drugs in the body lumen, as compared to relying on a single therapy with an increased dosage which may not be as effective. Moreover, an x-ray tube provides many advantages as it permits convenient dosing where the source may be easily turned on and off, eliminates the need to prepare, handle, and dispose of radioisotopes, and the like.
It will be appreciated that there are a number of means available for releasing any of the above described agents. Conventional intravascular delivery devices typically comprise a source of the agent, that may be external or internal to the device, and means for controlled drug release to the body lumen. Such means may comprise a porous material which contains the agent, wherein the agent may elute out at a controlled rate from the pores. Such means may alternatively comprise a matrix, membrane, barrier, or coating which includes the agent. Usually, such a matrix comprises a rate controlling material, wherein the rate controlling material controls the rate at which the agent is released from the matrix. Such means may further comprise an infusion lumen for agent release or a drug eluting stent or graft. Still further, such means may comprise a reservoir containing the agent and a cover over the reservoir. Typically, the cover comprises a matrix, membrane, or barrier which in turn controls the rate at which the agent is released from the reservoir.
In one embodiment, the means for releasing the agent may comprise at least one microporous balloon on the catheter body. It is presently preferred that such a one balloon embodiment be employed in the coronary arteries as these vessels are relatively limited in size. The microporous balloon is usually inflated with any of the above described agents and the agent is released at a controlled rate from the microporous balloon by elution from pores. The microporous balloon is preferably elastic and made from nylon, Pebax, polyurethane, or like materials.
In another embodiment, the means for releasing the agent may comprise a matrix, membrane, barrier, or coating formed over at least a portion of at least one balloon on the catheter body. The agent may be disposed in the matrix or on a surface of the balloon beneath the matrix. The matrix will typically comprise a rate controlling material, wherein the rate controlling material controls the rate at which the agent is released from or through the matrix. The rate controlling material may comprise degradable, partially degradable, nondegradable polymer, synthetic, or natural material. The matrix may degrade by bulk degradation, in which the matrix degrades throughout, or preferably by surface degradation, in which a surface of the matrix degrades over time while maintaining bulk integrity, to allow release of the agent. Alternatively, a nondegradable matrix may release the agent by diffusion through the matrix. Optionally, the rate controlling material may be porous so as to allow elution of the agent from pores.
The x-ray tube may be positionable within any of the above described balloons. Typically, the x-ray tube is translatable along an axial line through a center of the balloon. Any of the above described balloons may further comprise perfusion threading on an outer surface to allow for blood perfusion. Such threading may form a spiral, helical, or angled pattern on the balloon surface. The catheter of the present invention may alternatively be equipped with a perfusion lumen/port to permit blood flow past the balloon when inflated.
In a second aspect of the present invention, a combined radiation and agent delivery catheter for inhibiting hyperplasia generally comprises a catheter body having an infusion lumen for releasing an agent, a pair of axially spaced apart balloons on the catheter body, and an x-ray tube. The x-ray tube applies a radiation dose between the axially spaced apart balloons while the infusion lumen releases the agent therein. It is presently preferred that such a two balloon catheter embodiment be employed in the peripheral arteries as such a structure may help center and correctly position the x-ray source in the peripheral vessels, provide a pocket for drug delivery, and aid in uniform radiation dosimetry, as described in greater detail in copending U.S. patent application Ser. No. 09/653,444, assigned the assignee herein, the full disclosure of which is incorporated herein by reference.
In a third aspect of the present invention, a combined radiation and agent delivery device for inhibiting hyperplasia generally comprises a catheter body, an x-ray tube coupleable to the catheter body, a stent which is releasable from the catheter body, and a source of an agent on the stent. The x-ray tube may be positionable within the catheter body to deliver a radiation dose to a vascular region where the stent have been released while the stent releases the agent after the stent has been implanted in a body lumen. The stent may release the agent in a variety of conventional forms. For example, the stent may incorporate a rate controlling matrix, membrane, barrier, or coating to provide controlled release of the agent from the matrix. The agent will typically be disposed on or within the stent or within the matrix. Alternatively, the stent may incorporate a porous material which contains the agent, wherein the agent may elute out at a controlled rate from the porous material. Still further, the stent may incorporate a reservoir containing the agent and a cover over the reservoir. Typically, the cover comprises a matrix, membrane, or barrier which in turn controls the rate at which the agent is released from the reservoir.
In a fourth aspect of the present invention, methods for inhibiting hyperplasia are provided. One method includes releasing an anti-hyperplasia agent at a target region within the body lumen and directing x-ray radiation at the target region, wherein the agent and the x-ray radiation combine to inhibit hyperplasia. The xe2x80x9ctarget regionxe2x80x9d will be a length within a blood vessel which is at risk of hyperplasia, typically as a result of the initial intravascular intervention(s). The method may further comprise inflating a balloon at the target region, wherein the agent is released from the balloon. The balloon may be inflated with the agent so that the agent is released from an interior of the balloon through pores or the agent may be released from a surface of the balloon through a rate controlling matrix. The method may optionally comprise isolating the target region, wherein the agent is released into the isolated region. The isolating may comprises inflating a pair of axially spaced apart balloons or expanding a pair of axially spaced apart mechanical barriers. Typically, the x-ray source is positioned within the balloon or the isolated target region. Positioning of the x-ray tube generally comprises energizing the x-ray tube and translating the x-ray tube to traverse the target region. A total radiation dose in a range from about 4 Gy to 24 Gy, preferably from 14 Gy to 20 Gy is applied to the target region. The total amount of agent released will typically depend on the specific agent being delivered. The x-ray radiation dose and agent release may additionally be carried out simultaneously or sequentially.
A further method for combination radiation and agent delivery comprises positioning an x-ray tube and a stent at a target region in the body lumen. An x-ray radiation dose is applied to the target region and an agent is released from the stent to the target region.
In a fifth aspect of the present invention, kits comprising a catheter and instructions on how to use the catheter are provided. The kit may also include a source of the agent. The catheter may comprise any of the delivery structures described herein, while the instructions for use will generally recite the steps for performing one or more of the above described methods. The instructions will often be printed, optionally being at least in-part disposed on packaging. The instructions may alternatively comprise a videotape, a CD-ROM or other machine readable code, a graphical representation, or the like showing any of the above described methods.